Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

作     者：Yungang Wang Shouyan Deng Jie Xu Yungang Wang;Shouyan Deng;Jie Xu

作者机构：Institutes of Biomedical SciencesZhongshan-Xuhui Hospitaland Shanghai Key Laboratory of Medical EpigeneticsFudan UniversityShanghai 200433China Department of Laboratory MedicineThe First People's Hospital of Yancheng CityYancheng 224006China Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China 

出 版 物：《Cancer Biology & Medicine》 (癌症生物学与医学（英文版）)

年 卷 期：2020年第17卷第3期

页      面：583-598页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：This work was supported by the National Natural Science Foundation of China(Grant Nos.81874050,81572326,81322036,81421001,and 81902906) National Key R&D Program of China(Grant No.2016YFC0906002) Startup Research Funding from Fudan University(Grant No.2019XJ) Jiangsu Province's Medical Scientific Research Project(Grant No.H2019102). 

主　　题：Cancer immunotherapy membrane protein PROTAC targeted degradation 

摘      要：Cancer immunotherapy harness the body s immune system to eliminate cancer,by using a broad panel of soluble and membrane proteins as therapeutic targets.Immunosuppression signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies,but because of repopulation of the membranevia intracellular organelles,targets must be eliminated in whole cells.Targeted protein degradation,as exemplified in proteolysis targeting chimera(PROTAC)studies,is a promising strategy for selective inhibition of target proteins.The recently reported use of lysosomal targeting molecules to eliminate immune checkpoint proteins has paved the way for targeted degradation of membrane proteins as crucial anti-cancer targets.Further studies on these molecules modes of action,target-bindingwarheads,lysosomal sorting signals,and linker design should facilitate their rational design.Modifications and derivatives may improve their cell-penetrating ability and thein vivo stability of these pro-drugs.These studies suggest the promise of alternative strategies for cancer immunotherapy,with the aim of achieving more potent and durable suppression of tumor growth.Here,the successes and limitations of antibody inhibitorsin cancer immunotherapy,as well as research progress on PROTAC-and lysosomal-dependent degradation of target proteins,are reviewed.